A well established application of gelatin is the use as a colloid in solutions as substitutes for plasma. Such plasma substitutes can be used for controlling circulating blood volume in the management of shock resulting from for instance hemorrhages or burns. Care should be taken that the gelatin solution is made sterile, pyrogen and antigen free, and as the result of the average molecular size, is capable of maintaining a desired colloid osmotic pressure. In order to maintain a colloid osmotic pressure that is sufficient enough to have a sufficient amount of blood circulating and establish an efficient enough blood pressure over an adequate period of time, the average size of the gelatin molecules would be such that gelling becomes a problem.
To render gelatin suitable as a plasma expander, it has been chemically modified in such a way that gelability is drastically reduced. For this purpose it is known that gelatin can be simultaneously degraded and crosslinked, branched or inter-molecular bridges can be formed from the gelatin molecules. Probably the most successful modification is the preparation of succinylated gelatin as described in U.S. Pat. No. 2,827,419. A commercial preparation based on succinylated gelatin is currently available, known as Gelufusine®. The gelatin that is used is isolated from bovine origin and has an average molecular weight of 30,000. Other commercially available modified gelatines are Geloplasma® (‘poligelatin’) and Gelifundol® (‘oxipoligelatin’).
WO 01/34646 A2 describes recombinant gelatins structures of various molecular weights and various degrees of hydroxylation. A multitude of possible uses of the recombinant gelatins is claimed among which the use as a plasma expander. However, it does not provide information about which structures are adequate plasma expanders nor does it provide any specific recombinant gelatin in combination with its use as a plasma expander. Furthermore it is silent about methods to predictably control the duration of the oncotic effect of a plasma expander.
A disadvantage of the commercially used gelatin derivatives is that at least part of the administered gelatin leaves the circulatory system by transport over the blood vessel-wall by which their contribution to a stable clinical pattern is absent.
Another disadvantage of the commercially used gelatin derivatives is the fact that the gelatin used is isolated from animal sources such as animal bone and hide, in particular it is derived from bovine sources. Disadvantages of this material are the presence of impurities and the fact that the nature of the composition is not clearly defmed and thus not reproducible. This may impose additional screening to ensure that the derivatisation process results in a product with the desired properties and may require careful purification steps. An additional problem nowadays, especially in relation to gelatin isolated from bovine sources, is the risk of contamination of the gelatin with factors responsible for the occurrence of Bovine Spongiform Encephalitis (BSE). For this reason the use of gelatin in blood substitution products may be prohibited. At present at least for one product, a modified gelatin of bovine origin, it is known that as a precautionary measure the product is no longer commercially available.
Another disadvantage of the commercially used gelatin derivatives is the fact that the preparation of the gelatin fragments with the intended size does not result in fully homogeneous material but in a heterogeneous mixture of gelatin fragments around a targeted average molecular weight. The smaller fragments will leave the blood circulation system by an early (unwanted) clearance (high clearance rate) by which their contribution to a stable clinical pattern is absent and the nephrotic system is negatively imposed.
Another disadvantage of the presently used gelatin derivatives as colloidal additives in plasma substitution compositions is the occurrence of hypersensitivity reactions in subjects. In particular subjects having an allergy or an auto-immune disease, or for some other reason having an increased level of antibodies, in particular IgE antibodies, are at risk. A case of acute emergency in which the administration of plasma expanders is required is in subjects suffering from shock, more specific hypoglycemic shock due to severe bleeding, excessive fluid loss or inadequate fluid uptake. In such a situation there is simply no time to assess possible risk factors, such as the presence of an allergy. If a subject is known to have an allergy, prophylactic administration of an antihistaminic can be contemplated. However, in case of acute emergency, any kind of prophylactic treatment is uncalled for. The condition of immediate hypersensitivity, which can occur upon application of the presently used gelatin derivatives, is known as anaphylactic shock. This is a life-threatening condition where blood pressure is too low to sustain life, which in fact was the condition that should be counteracted by the plasma expander. Since a subject receiving the plasma expanders already suffers an acute trauma the condition of anaphylactic shock is most likely to be fatal.